YALE CENTER OF MOLECULAR DISCOVERY PROJECT SUMMARY/ABSTRACT In late 2011, Yale University combined 2 successful exisiting cores, Small Molecule Discovery Center and High Throughput Cell Biology, into a single core: Yale Center for Molecular Discovery (YCMD). YCMD was established to provide high-throughput and high-content screening and assay development, as well as medicinal chemistry services. YCMD works with individuals from Yale Cancer Center (YCC) and other Yale laboratories to design, optimize, and execute all phases of small molecule and siRNA screening in customized biochemical, cell-based, and model organism-based assays. YCMD synergizes existing technologies and expertise and helps expand the capabilities and impact of investigators? novel concepts by mining pathways or identifying small molecule leads in a cost-effective manner. As a YCC shared resource, YCMD offers services that span a range of investigator-driven goals and needs. During the most recent funding period, 49 laboratories have used YCMD. Thirty of these users (61%) were YCC members. This Shared Resource was most widely used by Developmental Therapeutics (DT), but nearly all of the YCC research programs benefited from this core. YCMD helped YCC members in basic and translational research address fundamental questions in biology. In pursuit of translational research, YCMD scientists discover novel small molecule probes that may serve as starting points for new therapeutics, to understand basic biological processes and to crystallize proteins in unique conformations that reveal their mechanisms of action. Crystal structures enable structure-based drug design to inform hypotheses for development of new molecules with increased binding, solubility, or attachment of linker groups. The Specific Aims of YCMD are to: (1) Facilitate new lines of research for YCC members and other Yale faculty; (2) Support early-stage development for translational research programs; and (3) Make the YCMD suite of technologies required for assay development and high-throughput screening accessible to a wide user base.